Genetic factors that contribute to Alzheimer's disease (AD) susceptibility are critical to our understanding and early diagnosis of the disease. A chromosome 10 region contains at least one susceptibility locus for late onset Alzheimer's disease, and is associated with increased amyloid-B (ADi) plasma levels. The gene encoding urokinase-type plasminogen activator (uPA) is within this implicated region. UPA is induced by AB-treated neurons in vitro and in the Hsiao mouse model of AB burden in vivo. Moreover, uPA converts plasminogen to the active protease plasmin, which degrades both nonaggregated and aggregated AB with physiologic efficiency. In summation, ADi induces uPA, which can in turn lead to AB degradation, suggesting a self-regulated system for clearance of AB aggregates. Considering these data overall we hypothesize that the chromosome 10 loci includes a uPA polymorphism(s) that modulates uPA's ability to contribute to AD clearance. To evaluate this hypothesis, we propose to (i) identify uPA polymorphisms that segregate with Alzheimer's disease. In preliminary work we have identified two uPA polymorphisms that significantly segregate with AD susceptibility and are in strong linkage disequilibrium, including (i) a substitution of leu for pro at position 141 within uPA, which alters binding of the uPA zymogen to aggregated fibrin and (ii) a SNP two basepairs 3' to an AP-I site that is known to be critical for uPA induction. We also propose to (ii) Gain insight into the possible role of the at-risk uPA haplotype by comparing individuals homozygous for each genotype for relevant clinical and neuropathologic markers of Alzheimer's disease, (iii) Evaluate the effect of the uPA polymorphisms associated with AD risk on uPA expression and function, and (iv) Evaluate the role of uPA in AB clearance in vivo by quantifying AB accumulation in mice that are wildtype or genetically deficient for uPA. Overall, the focused approach proposed here will (i) directly evaluate the possible role of uPA polymorphisms as a risk factor(s) for Alzheimer's disease, and (ii) provide insights into possible mechanisms underlying differential uPA actions. These studies are significant in that the identification of additional genetic risk factors for Alzheimer's disease will aid in early AD diagnosis, and thereby facilitate drug discovery by identifying patients at high risk for AD prior to symptomology. Moreover, by evaluating possible mechanisms underlying the enhanced susceptibility to Alzheimer's disease, these studies may lead to the discovery of novel insights into the molecular mechanisms underlying Alzheimer's disease, and thereby suggest new therapeutic approaches.